In a chimeric molecule, two or more molecules that exist separately in their native state are joined together to form a single entity (molecule) having the desired functionality of all of its constituent molecules. Frequently, one of the constituent molecules of a chimeric molecule is a "targeting molecule". The targeting molecule is a molecule such as a ligand or an antibody that specifically binds to its corresponding target, for example a receptor on a cell surface. Thus, for example, where the targeting molecule is an antibody, the chimeric molecule will specifically bind (target) cells and tissues bearing the epitope to which the antibody is directed.
Another constituent of the chimeric molecule may be an "effector molecule." The effector molecule refers to a molecule that is to be specifically transported to the target to which the chimeric molecule is specifically directed. The effector molecule typically has a characteristic activity that is desired to be delivered to the target cell. Effector molecules include cytotoxins, labels, radionuclides, other ligands, antibodies, drugs, prodrugs, liposomes, and the like.
In particular, where the effector component is a cytotoxin, the chimeric molecule may act as a potent cell-killing agent specifically targeting the cytotoxin to cells bearing a particular target molecule. For example, chimeric fusion proteins which include interleukin 4 (IL4) or transforming growth factor (TGF.alpha.) fused to Pseudomonas exotoxin (PE), interleukin 2 (IL2) fused to Diphtheria toxin (DT) have been shown to specifically target and kill cancer cells (Pastan et al., Ann. Rev. Biochem., 61: 331-354 (1992)).
The targeting moiety of these chimeric cytotoxins is often selected to pacifically target and bind to growth factor receptors, particularly those receptors that are overexpressed on cancer cells as compared to normal cells (e.g., Debinski et al. (1993) J. Biol. Chem., 268: 14065-14070, Phillips et al. (1994) Cancer Res., 54: 1008-1015, Debinski et al. (1994) Int. J. Cancer, 58: 744-748). However, even where the target receptor is overexpressed on cancer cells there is typically a significant level of receptor expression on normal cells as well. Therefore, even though one can obtain a therapeutic window for the cytotoxins, toxicities related to the presence of growth factor receptors on normal cells are dose-limiting for their administration (Phillips et al. (1994) Cancer Res., 54: 1008-1015, Debinski et al. (1994) Int. J. Cancer, 58: 744-748). It is thus desirable to identify targets or targeting ligands that show provide increased specificity for cancer cells as compared to normal cells and thereby improve the dosage levels that can be administered with diminished or no toxic side-effects.